Understanding how sensory stimuli in the environment are represented in our brains is a fundamental question in neuroscience. The olfactory system is an attractive sensory system to approach this question since the major anatomical pathways connecting receptor neurons, second-order mitral cells in the olfactory bulb, and tertiary neurons in olfactory cortex are straightforward and well understood. Intracellular recordings demonstrate that neural representations of odors in second-order neurons do not result exclusively from feedforward input from receptor cells but, instead, result from complex interactions between excitatory and inhibitory circuits. Little is known about the neural circuits that generate inhibition onto mitral cells, the most common second-order olfactory neuron. The present proposal uses rodent brain slice recording methods to determine how physiologically-relevant pathways excite olfactory bulb interneurons and inhibit mitral cells. Using both whole-cell intracellular recording and live 2-photon imaging methods, we will determine the relative effectiveness of orthodromic (sensory-driven) and cortical feedback pathways in exciting GABAergic granule cells. We will also test the hypothesis, arising from our publications from the previous funding period and preliminary studies, that coincident inhibitory input can synchronize discharges in inhibitory interneurons, generating large-amplitude IPSPs in mitral cells. Blanes cells, a new interneuron subtype we described recently, synapse on granule cells and, therefore, are ideally suited to mediate this interneuron synchronizing function. The proposed studies will define the excitatory pathways that normally activate Blanes cells and will test the hypothesis that these interneurons provide feedforward inhibition onto granule cells following cortical discharges. Defining the cellular mechanisms that generate sensory-evoked inhibition in the olfactory bulb, the overall focus of this proposal, is critical to understand how olfactory information is represented in the brain. The proposed studies also are significant as they represent an important step toward understanding the specific deficits in many major neurodegenerative diseases in which olfactory function is affected. In many of these diseases, olfactory impairments occur early in the disease onset. Insights into the specific olfactory mechanisms affected in these diseases may lead to directly testable hypotheses regarding analogous mechanisms in the cortical areas responsible for the cognitive deficits commonly associated with neurodegenerative disorders. PUBLIC HEALTH RELEVANCE: One of the fundamental questions in neuroscience is how activity of brain cells represents stimuli in the environment. The proposed research program seeks to define fundamental aspects of how olfactory stimuli are processed by the olfactory bulb, the primary olfactory brain region. Since olfaction is often impaired early in the course of neurodegenerative diseases, our work may lead to new insights into the core circuit functions affected in these conditions.